Our overall goal is to understand the means by which methamphetamine (Meth) induces functional immune system abnormalities, how these changes alter the response to viral infection, and how the unique pattern of T cell dysfunction resulting from Meth leads to defective immunity to HIV with increased systemic and central nervous system (CNS) disease. Our experiments comprise five specific aims, working systematically and progressively through basic mechanisms in rodents to highly translatable experiments in nonhuman primates. We will learn new information regarding the regulation of the immune system by Meth and its modulation of the host response to HIV. In addition to in vivo studies, we will perform quantitative phosphoproteomics of the signaling in T cells to identify the molecular mechanism whereby Meth alters CD8 T cell function. These combined studies will reveal mechanistic crosscurrents in complementary systems modeling Meth abuse and HIV infection in humans, allowing the identification of the networks of cells and signaling events which are perturbed due to the intersection of Meth and HIV.